Many investigations on steroid compounds have heretofore been made, and some steroid compounds are known to have pharmaceutical activity. Especially, 2-bromo-6.beta.,9.alpha.-difluoro-11.beta.,17.alpha.,21-trihydroxy-1,4-pre gnadien-3,20-dione-17,21-diester (hereinafter referred to as compound VII) are known to be good medicine. U.S. Pat. No. 4,226,862 describes that the compound VII has valuable pharmaceutical activity such as anti-inflammatory activity or anti-rheumarthritic activity, and that the compound VII rarely has side effects, such as decrease in body weight, accumulation of sodium, decrease in potassium, or suppression of adrenal glands and hypophysis, which would often be observed with various conventional steroids having physiological activity. Also, the other investigation reported that the compound VII can be administered by intra-articulational injection and thus it is an effective anti-rheumatic agent.
European Pat. No. 97328 and U.S. Pat. No. 4,525,303 disclose a method of preparing the compound VII using hydrocortisone-21-ester which is readily available as a starting compound. This method comprises the steps of; (1) dehydration of a hydroxy group at the 11-position of the starting compound, (2) acetylation of a hydroxy group at the 17-position, (3) bromhydrination at the 11-position, (4) epoxidation at the 11-position with a base, (5) cleavage of the epoxy compound with hydrogen fluoride, (6) oxidation of the hydroxy group at the 11-position, (7) ketalation, (8) reduction of the hydroxy group at the 11-position, (9) epoxidation of the double bond between the 5-position and the 6-position with a peracid, (10) cleavage of the epoxy compound with hydrogen fluoride. In this method, 6.beta.,9.alpha.-difluoro-5.alpha.,17.alpha.,21-trihydroxypregna-3,11,20-t rione-17,21-diesters or 6.beta.,9.alpha.-difluoro-5.alpha.,11.beta.,17.alpha.,21-tetrahydroxypregn a-3,20-dione-17,21-diesters can be synthesized from the starting compound above and then the compound VII can be prepared from the diesters above by the following steps; (11) dibromination at the 2-position of the diesters, ( 12) dehydrobromination and dehydration in an amide solvent in the presence of a metal halide at high temperature.
In step (11), dibromide compound can be obtained through monobromide compound, when the diesters and a large amount of bromine are reacted at high temperature for a short period time. However, on the occasion of scaling up, the dibromide compound cannot be prepared stably with high quality and yield, because a great deal of bromine cannot be poured quickly into the reaction system, and because the dibromide compound in which the bromine has been transferred from the 2-position to the 4-position is produced as impurity in the dibromination. Therefore, the above method is found disadvantageous in that the compound VII cannot be produced stably with high quality and yield, because the completion of reaction in step (12) depends on the purity of the dibromide compound produced in step (11), and because the dibromide compound tends to be decomposed with hydrogen bromide and water produced as impurity since the reaction proceeds at high temperature in step (12). The above method, also, has a problem of taking much time to purify the crude compound VII.
The above method is inadequate for preparing the compound 10 on an industrial scale or on the occasion of scaling up.